Preparation of amides and quinazoline derivatives

The invention relates to a process for the preparation of amides, comprising reacting amines with carboxylic acids in the presence of silicon amines. The resulting amides are useful as the precursors of anti-hypertension medicines.

An amide unit is a very common functional group and exhibits major features in several important natural products or artificial compounds. A number of compounds with the structure of an amide display a very important character in the synthesis of medicines. For example, these compounds are useful as intermediates or precursors in the synthesis of final medicines. For example, the N-acylalkylenediamines of formula (I′) or (II′) are amides and can be respectively used as the intermediates for the synthesis of the anti-hypertension medicines of formula (I) or (II).

Generally speaking, the synthesis of such type of anti-hypertension medicines is conducted by reacting the quinazolinyl chloride intermediate of formula (III)

with the N-acylalkylenediarnine intermediate of formula (I′) or (II′), to obtain a compound of formula (I) or (II).

As to the synthesis of the intermediate of formula (III), i.e. 4-amino-2-chloro-6,7-dimethoxyquinazoline, DE 2 847 623 and J. Med. Chem . 1987, 30, 49 have fully disclosed the synthesis procedures.

There are a number of known methods for the synthesis of amides. For example, they can be produced by the reaction of amines with esters, which involves known, basic organic chemical reactions. Under heating conditions, the reaction of a primary amine and an ester can directly produce an amide bond. However, such a reaction mostly needs to be conducted in the presence of solvents. As to the amidation reaction of a secondary amine and an ester, it needs to be conducted under the catalysis of Lewis acids, strong bases or enzymes, in addition to the presence of solvents.

The conventional methods for direct conversion of carboxylic acids to amides require either a very high reaction temperature (over 190° C.) or special coupling agents, such as carbodumides, phosphorus agents and uronium salts. These coupling agents require preparation and cause problems in isolation of the desired amidation products.

In recent years, several researchers have dedicated to use a variety of processes to synthesize new N-acylalkylenediarnine intermediates, in order to synthesize new anti-hypertension medicines. For example, DE 2 847 623 and J. Med. Chem . 1987, 30, 49 disclose:

Arch. Pharm . 1994, 327, 661 discloses:

Farmaco . 1996, 51, 551 , J. Med. Chem . 1977, 20, 146 and U.S. Pat. No. 4,026,894 disclose:

Org. Prep. Proced. Int . 1976, 8, 85 discloses:

J. Med. Chem . 1986, 29, 19 discloses:

U.S. Pat. No. 4,093,726 discloses:

In view of the above, conventional processes for the preparation of N-acylalkylenediamine intermediates have the following characteristics:

(1) The processes use the corresponding organic acids as starting materials, activate the starting materials to form acyl chlorides or higher active intermediates such as anhydrides, then react the acyl chlorides or anhydrides with diamines to obtain the desired N-acylalkylenediamines. The reaction procedures of these processes are too complicated and the Yield: is low (about 40%-70%). Also, these processes may produce waste chemicals causing environmental problems.

(2) Since the reactivity of acyl chlorides or anhydrides is very high, one of the amino groups in the diamines used needs to be protected by hydrogen chloride, hydrogen brormide, acetic acid or a tertiary butyloxycarbonyl compound to prevent diamides formation. Subsequently, the deprotection step is required to obtain the desired N-acylalkylenediamines.

Therefore, the object of the present invention is to provide a process for the preparation of amides with simple steps and high Yield:, which simply reacts amines and carboxylic acids in the presence of silicon amines to form amides in situ. The process of the invention does not require the conversion of acids to alkyl esters, neither does it require high reaction temperatures or additional agents.

The present invention relates to a process for the preparation of amides, which comprises reacting amines with carboxylic acids in the presence of silicon amines.

This invention further relates to a process for the preparation of quinazoline derivatives, which comprises reacting amines with carboxylic acids in the presence of silicon amines to obtain amides, and contacting the resulting amides with a quinazoline.

The present invention first relates to a process for the preparation of amides, which comprises reacting amines with carboxylic acids in the presence of silicon amines.

The amines suitable for the process for the preparation of amides of the present invention comprise the amines of the following formulae:

wherein R is the same or different and selected from hydrogen, C 1-6 alkyl, and C 2-6 alkenyl; preferably selected from hydrogen and C 1-6 alkyl; most preferably selected from hydrogen and methyl; X is CR or NR, R is as defined above; m is 2 or 3, preferably 2; n is 2 or 3, preferably 2; k is 1 to 8; preferably 3.

The carboxylic acids suitable for the process for the preparation of amides of the present invention comprise the carboxylic acids of the following formula:

wherein R 1 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, aryl, heterocyclyl, and

wherein Y is selected from hydrogen, C 1-6 alkyl, and C 2-6 alkenyl; R 1 is preferably selected from C 1-6 alkyl, phenyl, 4 to 7 membered heterocyclyl which contains 1 to 3 the same or different hetero atoms selected from nitrogen, oxygen and sulfur, and optionally fused with phenyl or heterocyclyl, and

wherein Y is straight or branch C 1-6 alkyl; Alk is unsubstituted or substituted alkylene, preferably unsubstituted, hydroxyl-substituted or methyl-substituted alkylene; h is 0 to 4, preferably 0 to 2.

The silicon amines suitable for the process for the preparation of amides of the present invention comprise the silicon amines of the following formula:

wherein R 2 is the same or different and selected from hydrogen, C 1-6 alkyl, and C 2-6 alkenyl, preferably unsubstituted C 1-6 alkyl; Z is selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, and silyl, preferably C 1-6 alkyl-substituted silyl. Most preferably, the silicon amine is 1,1,1,3,3,3-hexamethyldisilazane, abbreviated as HMDS.

The present invention further relates to a process for the preparation of quinazoline derivatives, comprising reacting amines with carboxylic acids in the presence of silicon amines to obtain amides, and contacting the resulting amides with a quinazoline of the following formula:

wherein R 7 , R 8 , R 9 and R 10 are independently selected from halogen, hydrogen, amino, C 1-8 alkyl, C 2-8 alkenyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, C 6-12 aryl, C 1-8 alkoxy, C 1-8 alkylthio and C 3-8 heterocyclyl.

The amines suitable for the process for the preparation of quinazoline derivatives of the present invention comprise the amines of the following formulae:

wherein R is the same or different and selected from hydrogen, C 1-6 alkyl, and C 2-6 alkenyl; preferably selected from hydrogen and C 1-6 alkyl; most preferably selected from hydrogen and methyl; X is CR or NR, R is as defined above; m is 2 or 3, preferably 2; n is 2 or 3, preferably 2; k is 1 to 8; preferably 3.

The carboxylic acids suitable for the process for the preparation of quinazoline derivatives of the present invention comprise the carboxylic acids of the following formula:

wherein R 1 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, aryl, heterocyclyl, and

wherein Y is selected from hydrogen, C 1-6 alkyl and C 2-6 alkenyl; R 1 is preferably selected from C 1-6 alkyl, phenyl, 4 to 7 membered heterocyclyl which contains 1 to 3 the same or different hetero atoms selected from nitrogen, oxygen and sulfur, and optionally fused with phenyl or heterocyclyl, and

wherein Y is straight or branch C 1-6 alkyl; Alk is unsubstituted or substituted alkylene, preferably unsubstituted, hydroxyl-substituted or methyl-substituted alkylene; h is 0 to 4, preferably 0 to 2.

The silicon amines suitable for the process for the preparation of quinazoline derivatives of the present invention comprise the silicon amines of the following formula:

wherein R 2 is the same or different and selected from hydrogen, C 1-6 alkyl, and C 2-6 alkenyl, preferably unsubstituted C 1-6 alkyl; Z is selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, and silyl, preferably C 1-6 alkyl-substituted silyl. Most preferably, the silicon amine is 1,1,1,3,3,3-hexamethyldisilazane, abbreviated as HMDS.

The term “C 1-6 alkyl” represents straight or branch alkyl having 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, iso-pentyl, tert-pentyl, and hexyl. The term “C 2-6 alkenyl” represents straight or branch alkenyl having 2 to 6 carbon atoms and having at least one double bond in any position, for example, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, and 5-hexenyl. The term “aryl” represents aromatic mono- or poly-cyclohydrocarbyl, for example, phenyl and naphthyl. The term “heterocyclyl” represents saturated, partially saturated, or unsaturated heterocyclyl, in which, in addition to carbon atoms, the ring additionally contains hetero atoms selected from oxygen, sulfur and nitrogen. The term “alkylene” represents substituent —CH 2 —. The term “silyl” represents substituent —SiH 3 . C 1-6 alkyl, C 2-6 alkenyl, aryl, heterocyclyl, alkylene, and silyl can be substituted with one or more substitutents such as C 1-6 alkyl and hydroxyl.

The amidation reactions of the present invention comprise adding silicon amines into the mixtures of amines and carboxylic acids in the present of nitrogen air under moderate temperatures (between 70-200° C., preferably 75-150° C.); stirring the mixtures for several hours till the amidation reactions complete; after cooling, distributing the mixtures in a proper solvent, such as the aqueous solution of chloroform and sodium hydrogen carbonate; washing the organic layer, for example, with water; drying, for example, with anhydrous sodium sulfate; and carrying to chromatography, to obtain the desired amide products. The Yield: is between 72-93%.

The feasibility of the present invention is illustrated by the following examples which are provided for illustration but not for limitation of the scope of the invention.